Role of Human Cerebrospinal Fluid Chemokines in the Invasiveness of Human Glioblastoma

项目总结 摘要胶质母细胞瘤(GBM)是成人最常见、最具侵袭性和增殖性的原发脑肿瘤。 手术、放疗和化疗相结合的治疗策略。GBM的高侵袭能力使总的 手术切除几乎是不可能的，导致极高的复发率。形成新肿瘤的能力 驻留在基底膜内称为脑肿瘤起始细胞(BTICs)的细胞亚群中。BTIC是无差别的 具有自我更新和多潜能的细胞，具有在体内形成肿瘤的额外能力。我们的团队和 其他人报告说，在初级基底膜中，那些位于侧脑室(LV)附近的基底膜存在 多个不同的特征，包括远处复发增加，这对患者的生存产生了负面影响。 左室近端肾小球基底膜病患者预后较差的原因尚不清楚。可能的解释可能是 累及脑脊液和脑室下区神经源性窝区的肿瘤 (SVZ)。在一项初步研究中，我们已经确定人类非癌症脑脊液在体外排斥BTICs的迁移。这些分子 在脑脊液中对这种影响负有责任的人还不清楚。在这里，我们建议研究BTIC和BTIC之间的相互作用 脑脊液的不同部分。我们推测，脑脊液可以诱导GBM细胞更具侵袭性。我们会 使用手术中的人体组织进行这项研究。完成这项研究后，我们将获得更好的 了解脑脊液对GBM细胞的影响，并将发现脑脊液中可能影响其的因素 BTICs与癌症进展。最终，我们希望揭示治疗干预的具体目标，从而导致 提高GBM患者的存活率。

PROJECT SUMMARY Glioblastoma (GBM) is the most common, aggressive and proliferative primary brain tumor in adults despite current therapeutic strategies that combine surgery, radio, and chemotherapy. The high invasive capacity of GBM makes total surgical resection virtually impossible, resulting in an extremely high recurrence rate. The ability to form a new tumor resides in a subpopulation of cells within the GBM called brain tumor initiating cells (BTICs). BTICs are undifferentiated cells with self-renewing and pluripotential capacity, with the added ability of forming tumors in vivo. Our group and others have reported that among primary GBMs, those located in close proximity to the lateral ventricles (LV) present multiple distinct features, including increased recurrence at distant locations, which negatively affect patients' survival. The cause for worse outcomes in patients suffering LV-proximal GBMs is not known. Possible explanations may involve the proximity of these tumors to the cerebrospinal fluid (CSF) and neurogenic niche in the sub-ventricular zone (SVZ). In a pilot study, we have determined that human non-cancer CSF repels BTICs migration in vitro. The molecules in the CSF responsible for this effect are not known. Here we propose to study the interactions between BTICs and different fractions of CSF. We hypothesize that CSF can induce a more aggressive behavior of GBM cells. We will perform this research using intraoperative human tissue. Upon completion of this study we will have gained a better understanding of the effects of CSF on GBM cells and will have discovered possible factors within CSF which influence BTICs and cancer progression. Ultimately, we hope to reveal specific targets for therapeutic intervention leading to increased survival in patients with GBM.